Synchronous BRAFV600E and MEK inhibition leads to superior control of murine melanoma by limiting MEK inhibitor induced skin toxicity

Gadiot, Jules; Hooijkaas, Anna I.; Deken, Marcel A.; Blank, Christian U.

doi:10.2147/ott.s52552

Cited by 9 publications

(7 citation statements)

References 29 publications

(72 reference statements)

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“…We have previously shown that synchronous BRAFi + MEKi leads to superior tumor control in an induced BRAF V600E /PTEN −/− mouse melanoma model as compared to either agent alone 46 . We confirmed this observation in a syngeneic BRAF V600E /PTEN −/− -driven transplantation model 47 .…”

Section: Resultssupporting

confidence: 80%

“…Recent preclinical work has indicated synergistic effects of synchronous BRAFi and ACT 24 . The observation that BRAFi + MEKi alleviates some BRAFi-induced toxicities, 46,53 provides another argument for combining BRAFi + MEKi with immune checkpoint blockade. However, this raised a concern about possible impairment of T cells functions upon MEKi 27 .…”

Section: Discussionmentioning

confidence: 99%

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Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma

et al. 2016

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Immunotherapy of advanced melanoma with CTLA-4 or PD-1/PD-L1 checkpoint blockade induces in a proportion of patients long durable responses. In contrast, targeting the MAPK-pathway by selective BRAF and MEK inhibitors induces high response rates, but most patients relapse. Combining targeted therapy with immunotherapy is proposed to improve the long-term outcomes of patients. Preclinical data endorsing this hypothesis are accumulating. Inhibition of the PI3K-Akt-mTOR pathway may be a promising treatment option to overcome resistance to MAPK inhibition and for additional combination with immunotherapy.We therefore evaluated to which extent dual targeting of the MAPK and PI3K-Akt-mTOR pathways affects tumor immune infiltrates and whether it synergizes with PD-1 checkpoint blockade in a BRAFV600E/PTEN−/−-driven melanoma mouse model. Short-term dual BRAF + MEK inhibition enhanced tumor immune infiltration and improved tumor control when combined with PD-1 blockade in a CD8+ T cell dependent manner. Additional PI3K inhibition did not impair tumor control or immune cell infiltration and functionality. Analysis of on-treatment samples from melanoma patients treated with BRAF or BRAF + MEK inhibitors indicates that inhibitor-mediated T cell infiltration occurred in all patients early after treatment initiation but was less frequent found in on-treatment biopsies beyond day 15.Our findings provide a rationale for clinical testing of short-term BRAF + MEK inhibition in combination with immune checkpoint blockade, currently implemented at our institutes. Additional PI3K inhibition could be an option for BRAF + MEK inhibitor resistant patients that receive targeted therapy in combination with immune checkpoint blockade.

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Section: Resultssupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma

et al. 2016

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“…Gadiot et al [ 39 ] have recently compared the efficacy in vivo of single treatment of mutant BRAF melanoma with vemurafenib alone, trametinib alone or the combination of vemurafenib and trametinib. While vemurafenib alone was able to control tumor growth only for a short period of 3–4 weeks after which relapses occur, the combination of vemurafenib and trametinib was able to control cancer growth for a longer time.…”

Section: Resultsmentioning

confidence: 99%

Combination of antibodies directed against different ErbB3 surface epitopes prevents the establishment of resistance to BRAF/MEK inhibitors in melanoma

Fattore

Malpicci

Marra³

et al. 2015

Oncotarget

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Patients with metastatic melanoma bearing V600 mutations in BRAF oncogene clinically benefit from the treatment with BRAF inhibitors alone or in combination with MEK inhibitors. However, a limitation to such treatment is the occurrence of resistance. Tackling the adaptive changes helping cells survive from drug treatment may offer new therapeutic opportunities. Very recently the ErbB3 receptor has been shown to act as a central node promoting survival of BRAF mutated melanoma. In this paper we first demonstrate that ErbB3/AKT hyperphosphorylation occurs in BRAF mutated melanoma cell lines following exposure to BRAF and/or MEK inhibitors. This strongly correlates with increased transcriptional activation of its ligand neuregulin. Anti-ErbB3 antibodies impair the establishment of de novo cell resistance to BRAF inhibition in vitro. In order to more potently ablate ErbB3 activity we used a combination of two anti-ErbB3 antibodies directed against distinct epitopes of its extracellular domain. These two antibodies in combo with BRAF/MEK inhibitors potently inhibit in vitro cell growth and tumor regrowth after drug withdrawal in an in vivo xenograft model. Importantly, residual tumor masses from mice treated by the antibodies and BRAF/ERK inhibitors combo are characterized almost exclusively by large necrotic areas with limited residual areas of tumor growth. Taken together, our findings support the concept that triple therapy directed against BRAF/MEK/ErbB3 may be able to provide durable control of BRAF mutated metastatic melanoma.

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“…In the murine melanoma model, trametinib demonstrated a powerful action in controlling tumor growth, despite a high grade of skin toxicity; in contrast, the combination of this MEK inhibitor with the BRAF inhibitor dabrafenib led to a reduction in toxicity, maintaining a high response rate in melanoma treatment [199].…”

Section: Mek Inhibitors In the Treatment Of Melanomamentioning

confidence: 99%

Targeting the ERK Signaling Pathway in Melanoma

Savoia

Fava

Casoni

et al. 2019

IJMS

124

107

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The discovery of the role of the RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era in the treatment of this tumor. Vemurafenib was the first specific kinase inhibitor approved for therapy of advanced melanomas harboring BRAF-activating mutations, followed by dabrafenib and encorafenib. However, despite the excellent results of first-generation kinase inhibitors in terms of response rate, the average duration of the response was short, due to the onset of genetic and epigenetic resistance mechanisms. The combination therapy with MEK inhibitors is an excellent strategy to circumvent drug resistance, with the additional advantage of reducing side effects due to the paradoxical reactivation of the MAPK pathway. The recent development of RAS and extracellular signal-related kinases (ERK) inhibitors promises to add new players for the ultimate suppression of this signaling pathway and the control of pathway-related drug resistance. In this review, we analyze the pharmacological, preclinical, and clinical trial data of the various MAPK pathway inhibitors, with a keen interest for their clinical applicability in the management of advanced melanoma.

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Synchronous BRAFV600E and MEK inhibition leads to superior control of murine melanoma by limiting MEK inhibitor induced skin toxicity

Cited by 9 publications

References 29 publications

Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma

Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma

Combination of antibodies directed against different ErbB3 surface epitopes prevents the establishment of resistance to BRAF/MEK inhibitors in melanoma

Targeting the ERK Signaling Pathway in Melanoma

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